The present invention generally relates to processes for producing polycyclic fused ring compounds. More specifically, the present invention relates to processes for the production of polycyclic fused ring compounds including the simultaneous protection of the C(7) and C(10) hydroxy groups of a polycyclic fused ring polyol having the taxane tetracyclic nucleus.
10-DAB (I), which is extracted from the needles of the English yew (taxus baccata L.) is a key starting material in the production of taxol (also known as paclitaxel) and docetaxel (Taxotere®), both of which are potent anticancer agents.

Conversion of 10-DAB to a cytotoxically active taxane requires selective derivatization of the C(13) hydroxy group to form a C(13) ester side chain. Because 10-DAB is a polyol and because each of these hydroxy groups is not equally reactive under a defined set of conditions, preparation of taxol or docetaxel from 10-DAB typically requires selective protection and/or derivatization of the C(7) and C(10) hydroxy groups before the C(13) side chain is attached.
Early strategies for the preparation of taxol, docetaxel and other taxanes from 10-DAB were based on the observation of Senilh et al. (C.R. Acad. Sci. Paris, IT, 1981, 293, 501) that the relative reactivity of the four hydroxy groups of 10-DAB toward acetic anhydride in pyridine is C(7)—OH>C(10)—OH>C(13)—OH>C(1)—OH. Denis et al. reported (J. Am. Chem. Soc., 1988, 110, 5917) selective silylation of the C(7) hydroxy group of 10-DAB with triethylsilyl chloride in pyridine to give 7-triethylsilyl-10-deacetyl baccatin (III) in 85% yield.
More recently, Holton et al. disclosed in U.S. Pat. No. 6,191,287 that the relative reactivity toward acetic anhydride as between C(7) and C(10) is different in the presence of a Lewis acid than it is in the presence of base. Holton et al. described processes for the selective derivatization of the C(7) or the C(10) hydroxy group of 10-DAB and other taxanes, wherein the C(10) hydroxy group may be protected or derivatized prior to the C(7) hydroxy group. Specifically, Holton et al. described a process for acylating or silylating the C(10) hydroxy group prior to acylating, silylating, or ketalizing the C(7) hydroxy group.
In U.S. Pat. No. 5,763,477, Duvvuri et al. disclose the preparation of various taxanes using, as a starting material, 14-β-hydroxy-10-DAB (II).
Before derivatizing the C(13) hydroxy group, a necessary step for the preparation of a cytotoxically active taxane, Duvvuri et al. protect the C(1), C(7), C(10), and C(14) hydroxy groups using a dimethyl acetal of an appropriate aldehyde or ketone or an enol-ether to form fused rings at C(14) and C(1) and at C(7) and C(10):
See, for example, Duvvuri et al., U.S. Pat. No. 5,763,477 at column 7, lines 23-52. After protecting the C(1), C(7), C(10), and C(14) hydroxy groups to form compound (III), Duvvuri et al. derivatize the C(13) hydroxy group to attach a side chain and then deprotect the C(1) and C(14) hydroxy groups and optionally the C(7) and C(10) hydroxy groups. Disadvantageously, however, Duvvuri et al. report relatively low conversion rates for the protection and deprotection steps (see, e.g., Duvvuri et al.'s Examples 1, and 11-14).
In U.S. Pat. No. 6,825,365, Chanteloup et al. disclose protecting the C(7) and the C(10) hydroxy groups of a baccatin III using a disiloxane substituted with sterically hindered isopropyl groups to form a fused ring at C(7) and C(10):
See, for example, Chanteloup et al., U.S. Pat. No. 6,825,365 at column 9, line 1 to column 10, line 44 and Example 22.
After protecting the C(7) and C(10) hydroxy groups to form compound (IV), Chanteloup et al. treat the protected compound with an isoserine or oxazoline side chain precursor to derivatize the C(13) hydroxy group. When oxazoline side chain precursors are utilized, the oxazoline ring may be optionally opened by hydrolysis after the attachment of the side chain at the C(13) position of the protected baccatin III. See, e.g., Chanteloup et al., U.S. Pat. No. 6,825,365 at columns 10-14. Disadvantageously, Chanteloup et al. report relatively low conversion rates for the protection steps, fail to disclose any non-sterically hindered bifunctional protecting groups, and report no method for removal of the bifunctional protecting group (see, e.g., Chanteloup et al.'s Examples 14-22 and 29).